We address the role of phagocytes in acute and chronic lung injury. In acute injury, neutrophils, activated by humoral factors (e.g. C5a), aggregate, release lysosomal enzymes, generate O2- and form eicosanoids mainly via lipoxygenase pathways. It is not clear, however, which of these mediators is critical to tissue injury marked by leukoaggregation of the Adult Respiratory Distress Syndrome. We will compare intact neutrophils and their granule-free cytoplasts (neutroplasts) for their capacity to injure endothelial substrates in vitro. Neutroplasts cannot release lysosomal proteases or myeloperoxidase, but can aggregate and generate O2-. We can thus determine whether lysosomal proteases and the myeloperoxidase/H2O2 system are necessary for endothelial injury, or whether aggregation and O2- generation suffice. Differences with respect to lipoxygenase products formed by intact neutrophils and neutroplasts will permit dissection of the role of neutrophil eicosanoids in cell activation and endothelial injury. Since platelets augment neutrophil aggregation and cytotoxicity, we will determine how platelet-neutrophil interactions influence formation of leukotriene B4 (LTB4) and its antagonist, 5S, 12SdiHETE, and whether these products interact with several protein kinases and phosphoprotein phosphatases. we will also study in vitro correlates of chronic lung disease by exposing neutrophils and mononuclear phagocytes to crystals of silica and asbestos. We will determine relations between the membranolytic potential of crystals and their capacity to release LTB4 from phagocytes-as urate crystals can from neutrophils. We will determine whether colchicine, recently found to be a specific inhibitor of LTB4 synthesis in urate-stimulated neutrophils, inhibits LTB4 formation after silica or asbestos. Finally, we will test a novel hypothesis as to the mode of action of nonsteroidal antiinflammatory drugs (NSAID). Cyclooxygenase products (e.g. PGE2, PGI2) inhibit phagocyte functions whereas some lipoxygenase products (esp. LTB4) are potent stimulants. But other lipoxygenase products (5S, 12S, diHETE or 14, 15 diHETE) antagonize LTB4. We propose that exogenous NSAID divert arachidonate to yield antiinflammatory eicosanoids: "the body's own NSAID." These products will be sought in phagocytes treated with aspirin-like drugs. We will test this hypothesis by means of marine sponge cells which do not respond to stable prostaglandins, but whose LTB4-mediated aggregation is, surprisingly, inhibited by exogenous NSAID.